The term long term potentiation, or LTP, refers to a strengthening of synaptic connections between two neurons following intense, repetitive stimulation of the presynaptic neuron. Most neuroscientists think this process plays a fundamental role in learning and memory at the cellular level. This article will offer some historical perspective on the discovery of LTP in the context of neuroscience’s ongoing quest to answer a profound question: how does the brain learn and remember information?
The idea that the brain is responsible for thoughts and memory goes back to ancient times, appearing in the works of Hippocrates in the 4th century BCE. For the next 23 centuries, the mechanisms underlying learning and memory remained unknown; nevertheless, a general consensus emerged that the brain could somehow perceive, respond, and adapt to environmental stimuli. By the 19th century, neuroscientists proposed that electrical, chemical, and possibly structural changes in the brain accompanied learning and memory. That was about as far as neuroscience would progress until the mid-20th century. Even at this late date, many scientists resisted the idea that an adult’s brain’s structure could change in response to novel or repetitive stimuli.
In 1949, the paradigm began to shift after Donald Hebb proposed that synaptic connections within neural networks become strengthened when neurons fire frequently. Conversely, unused or seldom used synaptic connections tend to weaken over time and may disappear entirely. Hebb’s hypothesis is often expressed as the quote “Cells that fire together wire together”.
Although Hebb’s emphasis on synaptic plasticity was slow to gain acceptance, in retrospect it marked the dawn of a new era in neuroscience. The next major breakthrough came n 1968 when Terje Lomo and Tim Bliss demonstrated LTP induction in the hippocampus, a region of the brain’s temporal lobes involved in the consolidation of long term memories.
The search for the retrograde messenger in LTP
Although the basic sequence of LTP was understood by the early 1970’s, many puzzles remain unsolved. Chief among these is an adequate explanation for the changes in the presynaptic neuron underlying its enhanced ability to release neurotransmitter (NT). In other words, scientists agree that a hallmark event in LTP is increased presynaptic NT release, but the molecular mechanisms remain obscure.
By the early 1990’s, several theories had been proposed; nearly all of them invoked retrograde signaling from the postsynaptic neuron to the presynaptic cell. Some scientists focused on the excitatory NT glutamate along with calcium ions. Supposedly, after the presynaptic neuron fires a sufficient number of action potentials, the backwash of one or both substances onto the presynaptic cell induces LTP.
Other scientists turned their attention to smaller, more exotic molecules including soluble gases like nitric oxide or carbon monoxide; the membrane lipid arachidonic acid; the energy carrier ATP (adenosine triphosphate); PAF (Platelet Activating Factor), and others. Predictably, the debate generated more heat than it did light, and at present, no consensus exists as to the molecular mechanisms responsible for the induction phase of LTP.
New directions
In recent years, some researchers have focused on the long term preservation of LTP, with a particular emphasis on brain derived neurotrophic factor (BDNF). This protein, a member of the nerve growth factor family, seems to play many important roles in the CNS, including neuronal survival. In regards to LTP, BDNF may play a presynaptic role, enabling neurons to sprout new axonal connections and enlarge existing synaptic terminals. BDNF may also promote dendrite outgrowth on postsynaptic neurons, although a host of other protein growth factors are likely to play important roles as well.
